The signal transduction pathways driving morphogenesis and migration are not well understood, yet defects in these processes underlie a wide spectrum of human diseases and syndromes, including mental retardation, Wiskott-Aldrich syndrome, faciogenital dysplasia, hearing loss and cancer. The long term objectives of this proposal are to delineate the cellular mechanisms that control morphogenesis and migration. The approaches used here involve: (i) disrupting cell-cell contacts in tissue culture monolayers to induce polarized migration and (ii) promoting cell-cell contact between epithelial cells to induce polarized morphogenesis. The key hypothesis is that despite being very different biological processes, morphogenesis and migration share many of the same molecular components and signaling pathways and that Rho GTPases play a central role in both. Disrupting cell-cell contacts in fibroblast monolayers to induce migration activates Rho GTPase- dependent signal transduction pathways that lead to polarization of the actin and microtubule cytoskeletons along an anterior/posterior axis. Preliminary work has shown that Wnt5a and the intracellular adaptor protein disheveled are also required for polarization of both cytoskeletal networks and in Aim I, the biochemical relationship between Rho GTPases and Wnt pathways will be determined. In Aim II, the Rho GTPase pathways regulating apical-basal polarity during morphogenesis and anterior-posterior polarity during migration will be identified in epithelial cells. The spatially localized activation and responses of Rho GTPases are mediated by a family of 82 guanine nucleotide exchange factors (GEFs), 67 GTPase activating proteins (GAPs) and some 100 target proteins. The GEFs, GAPs and targets involved in controlling epithelial cell migration and morphogenesis will be identified. This program of research will lead to a significant advance in understanding the control of migration and morphogenesis and provide a basis for new therapeutic opportunities in a wide range of human disorders.Public Health Relevance: In the embryo, cells must migrate to appropriate locations and adopt specialized shapes to form organized tissues and organs. These structures then need to be maintained throughout adult life. The biochemical mechanisms controlling these processes are poorly understood, but defects contribute to a wide range of congenital and acquired human disorders, ranging from mental retardation to cancer.